Official Title: “The Efficacy of 17Beta-Estradiol in Postpartum-Related Depressive Illness”

This study evaluates the efficacy of estrogen treatment in women with postpartum depression (PPD).

PPD causes significant distress to a large number of women; the demand for effective therapies to treat PPD is considerable. Estradiol therapy has a prophylactic effect in women at high risk for developing PPD. The prevention of a decline in estradiol levels may prevent the onset of PPD. Studies also suggest that estradiol has antidepressant effects in women and may provide a safe and effective alternative to traditional antidepressants in women with PPD.

Participants will be screened with a medical history, physical examination, blood and urine tests, psychological tests, genetic studies, and self-rating scales and questionnaires. Upon study entry, women will be randomly assigned to wear skin patches containing either estradiol or placebo (a patch with no active ingredient) for 6 weeks. Women who receive estradiol and do not menstruate during the last week of the study will receive progesterone for 7 days to initiate menstruation. Women who receive placebo and do not menstruate during the last week of the study will continue to receive placebo at the end of the study. Every week, participants will have blood taken and will be asked to complete symptom self-rating scales.

A urine sample and blood samples will be collected at different time points through out of the study. Participants who receive placebo and those whose symptoms do not improve with estradiol therapy will be offered treatment with standard antidepressant medications for 8 weeks at the end of the study.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Efficacy Study

Postpartum-related mood disorders cause significant distress to a potentially large number of women. The demand for effective therapies for treating these mood disorders is considerable, as is the need to define clinical or biologic markers that may predict successful response of these mood disturbances to estradiol. Despite the prevalence of postpartum depressions, only one double-blind, placebo-controlled trial of a single psychotropic agent has been performed in this condition. Similarly, despite evidence of estradiol's therapeutic efficacy in trials that were both open (monotherapy) (1) and controlled (combined with traditional antidepressant agents (2), the potential of estradiol to be an effective alternative to traditional psychotropics in postpartum depression has not been examined under controlled conditions.

Postpartum depressions occur by definition after delivery when women are relatively hypogonadal. Indeed, plasma estradiol and progesterone levels are low and comparable to those seen during the peri and postmenopause. However, there is no evidence that postpartum depression represents a simple hormone deficiency, and women with postpartum depression are not distinguished from women without postpartum depression on the basis of any abnormality of basal reproductive hormones. Nonetheless, a role for declining estradiol secretion has been suggested by the following observations: 1) estradiol therapy has been reported to have a prophylactic effect in women at high risk for developing postpartum depression (3), suggesting that the prevention of a decline in estradiol levels (threshold or rate of decline) may prevent the onset of postpartum depression in some women; and (2) declining ovarian steroids trigger the onset of mood disturbances in women with but not women without a history of postpartum depression during a scaled down model of pregnancy in the puerperium (4). Thus, as with depressions occurring during the perimenopause, when ovarian hormone secretion is also declining, postpartum depression may also be responsive to estradiol therapy. In fact, open trials of estradiol therapy in postpartum depression (1) as well as a trial of estradiol in combination with traditional antidepressants (2) have suggested that estradiol does have antidepressant-like effects that are observed within a three week period in women with postpartum onset major depression. Thus, estradiol treatment may not only provide a safe and effective alternative to traditional antidepressants in women with postpartum depression, but it may also suggest the relevant hormonal trigger for the development of this condition.

In this protocol we wish to investigate the effects of estradiol on mood in women with moderately severe postpartum depression under placebo controlled conditions. This protocol will address the following question: 1) Does estradiol improve mood in postpartum depressed women?

Intervention(s) in this Clinical Trial

• Drug: 17 beta-estradiol
  • Alora 100 microgram per day by skin patch for 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Experimental
• Placebo Comparator: 2
  • Placebo comparator

Primary Measures

• Edinburgh Postnatal Depression Scale (2) the 17-item Hamilton Depression Rating Scale (HDRS).
  • Time Frame: Weekly (main outcomes at 2 and 6 weeks)
    

Secondary Measures

• Beck Depression Inventory (BDI), the Center for Epidemiologic Studies-Depression Scale (CES-D); visual analogue scale (VAS) measuring the reported severity of 15 mood and behavioral symptoms; SCID interview.@@@
  • Time Frame: Weekly (main outcomes at 3 and 6 weeks)
    

INCLUSION CRITERIA:

Subjects for this study will meet the following criteria:

• 1. A history of at least two weeks with postpartum-related mood disturbances of moderate severity, and self-report of the onset of depression within three months of a normal vaginal delivery or uncomplicated Caesarean section;
• 2. A current episode of minor (meeting 3-4 criterion symptoms) or major depression (of moderate severity or less on the SCID severity scale and not meeting DSM-IV criteria symptom 9 [suicidal ideation]) as determined by the administration of the minor depression module of the SADS-L and the Structured Clinical Interview for DSM-IV.
• Additionally, to ensure that subjects meet a minimum threshold for severity of depression, subjects will have scores greater than or equal to 10 on either the Beck
• Depression Inventory (BDI) or the Center for Epidemiologic Studies - Depression (CES-D) Scale during at least three of the six clinic visits during the two week screening phase, as well as a 17 item Hamilton Depression score greater than or equal to 10. Subjects will be excluded if they meet any of the following criteria: major depression of greater than moderate severity (including postpartum psychosis). DSM-IV criteria #9 (suicidal ideation), or anyone requiring immediate treatment after clinical assessment.
• 3. Not greater than six months post delivery;
• 4. Age 20 to 45;
• 5.) No prior hormonal therapy for the treatment of postpartum-related mood or physical symptoms within the last six months;
• 6) No history of psychiatric illness during the two years prior to the reported onset of the current episode of depression;
• 7) In good medical health, and not taking any medication or dietary and herbal supplements on a regular basis (with the exception of multivitamins or calcium supplements).

EXCLUSION CRITERIA:

• The following conditions will constitute contraindications to treatment and will preclude a subject's participation in this protocol:
• 1) severe major depression with any of the following:
• 1. positive (threshold) response to SCID major depression section item # 9, suicidal ideation;
• 2. anyone requiring immediate treatment after clinical assessment;
• 3. severity ratings greater than moderate on the SCID IV interview (including postpartum psychosis);
• 2) current treatment with antidepressant medications
• 3) history of psychiatric illness during the two years before the reported onset of the current episode of depression or a history of either mania (DSM-IV criteria) or postpartum psychosis at any time in the past.
• 4) history of ischemic cardiac disease, pulmonary embolism, retinal thrombosis, or thrombophlebitis; any subject with risk factors for thrombo-embolic phenomena including cigarette smokers (greater than 10 cigarettes per day), varicose veins, patients with prolonged periods of immobilization (including prolonged travel), and active heart disease.
• 5) renal disease, asthma
• 6) hepatic dysfunction
• 7) women with a history of carcinoma of the breast, or women with a family history of the following: premenopausal breast cancer or bilateral breast cancer in a first degree relative; multiple family members (greater than three relatives) with postmenopausal breast cancer
• 8) women with a history of uterine cancer, endometriosis, ill-defined pelvic lesions, particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding
• 9) patients with a known hypersensitivity of estradiol, Alora, or medroxyprogesterone acetate
• 10) pregnant women
• 11) porphyria
• 12) diabetes mellitus
• 13) cholecystitis or pancreatitis
• 14) history of cerebrovascular disease (stroke), epilepsy, hypertension, hypercalcemia
• 15) recurrent migraine headaches
• 16) malignant melanoma
• 17) history of familial hyperlipoproteinemia

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: 45 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: National Institute of Mental Health (NIMH)

Overall Clinical Trial Officials and Contacts

Overall Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00059228

Study ID Number: 030161

ClinicalTrials.gov Identifier: NCT00059228

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page